The central theme of the Program Project is to understand the innate host defense mechanisms against inhaled pathogens by the two pulmonary collectins, surfactant proteins A and D (SP-A, SP-D). This understanding is important not only in the context of prevalent respiratory infections but also those associated with serious global biothreats [unreadable] the emergence of antibiotic-resistant organisms;evolution and rapid spread of more lethal respiratory viruses;and potential use of inhaled pathogens in acts of bioterrorism. Effective pulmonary host defense requires early recognition of microorganisms. Following deposition of an organism into the respiratory tract, there is a critical window of opportunity for pathogen clearance;delayed response favors infection. The pulmonary collectins play a front-line role in the innate defense against many gram-negative and positive bacteria and their endotoxins, mycobacteria, pathogenic fungi, and obligate intracellular pathogens including influenza A (lAV) and other potentially lethal viruses. The innate defense properties of pulmonary collectins depend upon their rapid recognition and, in some cases, neutralization of inhaled microorganisms based on pattern recognition of highly-conserved microbial surface components such as N-linked high-mannose glycans on lAV and gram-negative lipolysaccharide (endotoxin). Other studies show that animals deficient in lung collectins show significantly increased susceptibility to microbiological challenges. Studies of recombinant truncated SP-A and SP-D in murine models of allergy and infection have offered the possibility that aerosolized forms of these proteins delivered by inhalation may have therapeutic potential in controlling respiratory infection, inflammation, and allergy in humans. In this program project, a highly collaborative and focused group of projects using complementary approaches, including x-ray crystallography, mutagenesis, spectroscopy, in vitro and in vivo analyses using animal models, aim specifically at innate responses of collectins, and proteins such as KGF that modulate their activity, to lAV and gram-negative bacteria both to gain mechanistic understanding and assist design of potential collectin-based therapeutics with increased antimicrobial activities. .